Epileptic Encephalopathy, Early Infantile, 55

A number sign (#) is used with this entry because of evidence that early infantile epileptic encephalopathy-55 (EIEE55) is caused by compound heterozygous or homozygous mutation in the PIGP gene (605938) on chromosome 21q22.

For a general phenotypic description and a discussion of genetic heterogeneity of EIEE, see EIEE1 (308350).

For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).

Clinical Features

Johnstone et al. (2017) reported 2 sibs, born of unrelated parents of European ancestry, with early infantile epileptic encephalopathy. The patients presented in the first weeks of life with refractory seizures. EEG showed various abnormalities, including focal-spreading sharp waves, multifocal epileptiform discharges, slow background activity, and modified hypsarrhythmia. The older patient showed progressive growth impairment and small head circumference (less than 2nd percentile). Brain imaging showed thin corpus callosum and abnormal T2-weighted signals in the periventricular and subcortical white matter. At age 10 years, he had profound intellectual disability with little purposeful movements, no head control, no speech, central hypotonia, peripheral hypertonia, and feeding difficulties necessitating a G-tube. His younger sister had a similar disorder with refractory seizures, no eye contact or tracking, and hypotonia with fisted hands, clonus, and hyperreflexia. She died at age 26 months. Both patients had cortical visual impairment.

Krenn et al. (2019) reported a girl, born of unrelated Polish parents, with EIEE55. The neonatal period was complicated by lethargy and poor feeding. Her first seizure occurred at 7 months of age and was associated with status epilepticus and EEG sharp waves. She continued to have refractory seizures and showed global developmental delay and hypotonia. At age 2 years, she was unable to speak and had not achieved sitting or crawling. Brain imaging showed transient diffusion-weighted abnormalities and hippocampal asymmetry.

Inheritance

The transmission pattern of EIEE55 in the family reported by Johnstone et al. (2017) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 sibs with early infantile epileptic encephalopathy-55, Johnstone et al. (2017) identified compound heterozygous mutations in the PIGP gene isoform 1 (M25T, 605938.0001 and c.456delA, 605938.0002). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient fibroblasts showed decreased PIGP mRNA and presumably decreased protein levels, as well as decreased cell surface expression of GPI-anchored proteins; this defect could be rescued by overexpression of PIGP isoform 2. The findings implicated a role for PIGP and GPI-anchored proteins in neurodevelopment.

In a Polish girl with EIEE55, Krenn et al. (2019) identified a homozygous frameshift mutation in the PIGP gene (c.456delA; 605938.0002). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Flow cytometric analysis of patient lymphocytes showed decreased expression of GPI-anchored proteins, suggesting a loss-of-function effect. The findings confirmed PIGP as a monogenic disease causing developmental and epileptic encephalopathy.